Risk of pneumonia and other complications of influenza-like illness in patients treated with oseltamivir

ABSTRACT

Background: Clinical trials suggest that the risk of pneumonia and other sequelae of influenza may be reduced in patients using oseltamivir.

Research design and methods: This retrospective cohort study used U.S. health insurance claims data. Patients were grouped into three cohorts: (1) diagnosed with influenza-like illness (ILI) and received a dispensing of oseltamivir; (2) diagnosed with ILI but received no antiviral medication; and (3) received oseltamivir without a physician diagnosis of ILI. Baseline factors assessed included demographics, history of drug dispensings, diagnoses, and vaccinations.

Main outcome measures: Outcomes included diagnosis of pneumonia, dispensing of an antibiotic, or hospitalization within 30 days after an ILI diagnosis or oseltamivir dispensing.

Results: The adjusted hazard ratio for ILI with oseltamivir compared to ILI without antivirals for pneumonia was 0.72 (95% CI, 0.60–0.86), for antibiotic dispensing was 0.89 (95% CI, 0.86–0.93), and for hospitalization was 0.74 (95% CI, 0.61–0.90). The cohort who received oseltamivir without an ILI diagnosis did not differ significantly in risk of any outcome from the ILI with oseltamivir cohort.

Conclusions: The risk of pneumonia, antibiotic dispensing, and hospitalization was reduced in patients with ILI who received oseltamivir compared to no antiviral therapy. These findings were based on health care claims only and have not been verified through medical record review.     

Risk of pneumonia and other complications of influenza-like illness in patients treated with oseltamivir

BACKGROUND: Clinical trials suggest that the risk of pneumonia and other sequelae of influenza may be reduced in patients using oseltamivir. RESEARCH DESIGN AND METHODS: This retrospective cohort study used U.S. health insurance claims data. Patients were grouped into three cohorts: (1) diagnosed with influenza-like illness (ILI) and received a dispensing of oseltamivir; (2) diagnosed with ILI but received no antiviral medication; and (3) received oseltamivir without a physician diagnosis of ILI. Baseline factors assessed included demographics, history of drug dispensings, diagnoses, and vaccinations. MAIN OUTCOME MEASURES: Outcomes included diagnosis of pneumonia, dispensing of an antibiotic, or hospitalization within 30 days after an ILI diagnosis or oseltamivir dispensing. RESULTS: The adjusted hazard ratio for ILI with oseltamivir compared to ILI without antivirals for pneumonia was 0.72 (95% CI, 0.60-0.86), for antibiotic dispensing was 0.89 (95% CI, 0.86-0.93), and for hospitalization was 0.74 (95% CI, 0.61-0.90). The cohort who received oseltamivir without an ILI diagnosis did not differ significantly in risk of any outcome from the ILI with oseltamivir cohort. CONCLUSIONS: The risk of pneumonia, antibiotic dispensing, and hospitalization was reduced in patients with ILI who received oseltamivir compared to no antiviral therapy. These findings were based on health care claims only and have not been verified through medical record review.     

炎琥宁治疗儿童甲型H1N1流感临床诊断住院病例47例临床体会

目的：分析重庆医科大学附属儿童医院甲型H1N1流感临床诊断住院病例的临床特征，以及中药炎琥宁注射液与奥司他韦抗病毒治疗的疗效。方法：收集2009年9月-11月我院收治的甲型H1N1流感患儿，分析年龄、性别、临床症状体征、实验室辅助检查、胸部影像学检查、抗病毒治疗及其它治疗的疗效。结果：符合甲型H1N1流感诊断的患儿共47例，男24，女23例，平均7．11岁；47例均有发热，且均为中高热，发生肺炎28例（59．57％）；所有患儿均静脉给予炎琥宁注射液10mg／（kg·d），〈0．4g/d，1次／d，部分病情较重者加用奥司他韦治疗，并辅以其它口服中成药，合理选用抗生素，结合对症支持治疗；体温恢复至正常平均时间（2．02±0．27）d，所有患儿均治愈出院，平均住院日（6．49±0．59）d。结论：炎琥宁注射液与奥司他韦用于不同病情甲型H1N1流感患儿均获得满意疗效。     

Oseltamivir for treatment and prophylaxis of influenza infection

Background: Influenza infection is a global problem affecting millions of people worldwide, despite efficacious vaccines. Treatment and prophylaxis against influenza have been successful using antiviral medications such as adamantanes and neuraminidase inhibitors. Objective: To review the antiviral agents and specifically the neuraminidase inhibitor, oseltamivir, for use in treatment and prophylaxis of influenza infection. Methods: This review focuses on published literature regarding the clinical use of oseltamivir, as well as discussing emerging threats such as avian influenza, antiviral resistance, and strategies such as combination antiviral treatment to mitigate these threats. Results: Oseltamivir is effective in reducing symptom burden in those with influenza A or B infection, and is preventative against developing infection after exposure. Emergence of naturally occurring or post-treatment oseltamivir-resistant influenza as well as an avian influenza pandemic may limit its future use as a monotherapeutic antiviral treatment agent.     

A multicentre,randomized, controlled trial of oseltamivir in the treatment of influenza in a high-risk Chinese population

ABSTRACT

Objective:?To evaluate the efficacy and safety of oseltamivir treatment in a population at high risk for influenza.

Research design and methods:?This was a randomized, open-label, controlled trial involving Chinese patients with chronic respiratory diseases (chronic bronchitis, obstructive emphysema, bronchial asthma or bronchiectasis) or chronic cardiac disease. Patients showing symptoms of influenza were randomly assigned to receive oral oseltamivir 75?mg twice daily for 5 days (oseltamivir group), or symptomatic treatment (control group) within 48?h after symptom onset.

Main outcome measures:?The main outcome measures were duration and severity of illness in influenza-infected patients. Other outcome measures included incidence of complications, antibiotic use, hospitalization and total medical cost.

Results:?Of the 118 recruited patients, 56 were identified as influenza-infected through laboratory tests (oseltamivir, N = 27; control, N = 29). Relative to symptomatic treatment, oseltamivir significantly reduced the duration of influenza symptoms by 36.8% (?p = 0.0479), and the severity by 43.1% (?p = 0.0002). In addition, oseltamivir significantly reduced the duration of fever by 45.2% (?p = 0.0051), and the time to return to baseline health status by 5 days (?p = 0.0011). The incidence of complications (11% vs. 45%, p = 0.0053) and antibiotic use (37% vs. 69%, p = 0.0167) were also significantly lower in the oseltamivir group compared with the control group. The cost of treating influenza and its complications was comparable between the two groups (?p = 0.2462).

Conclusions:?Oseltamivir is effective and well tolerated in high-risk patients with chronic respiratory or cardiac diseases. It can reduce the duration and severity of influenza symptoms and decrease the incidence of secondary complications and antibiotic use, without increasing the total medical cost.     

基于真实世界数据的磷酸奥司他韦临床使用情况及安全性分析

目的 调查磷酸奥司他韦临床使用情况及安全性,分析其药品不良反应(ADR)的发生特点,为合理用药提供参考.方法 回顾性分析我院2016年2月1日至2018年2月28日门诊及住院患者使用磷酸奥司他韦的病例用药情况,对适应证、用药目的 、用法用量、联合用药及ADR进行统计分析,重点关注其用药合理性及安全性.探讨ADR与年龄、...     

The effect of adjunctive mood stabilizers on antipsychotic utilization pattern and health resource utilization for Medicaid enrollees with schizophrenia

ABSTRACT

Background: Prescribing adjunctive mood stabilizers to manage schizophrenia is prevalent, despite the lack of substantial evidence to support the long-term use of this treatment regimen.

Objective: The objective of this study was to assess the impact of using adjunctive mood stabilizers on antipsychotic utilization, total health expenditures, inpatient hospital­izations, long-term care stays, and emergency room (ER) visits for patients with schizophrenia.

Methods: Georgia Medicaid claims from 1999 through 2001 were analyzed to identify recipients diagnosed with schizophrenia (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD?9?CM]: 295.XX). The treatment groups consisted of subjects who received combination therapy of mood stabilizers and anti­psychotics (including both atypical and typical medica­tions), while the comparison group consisted of subjects who were on antipsychotic medications without exposure to the mood stabilizers under investigation. Four treatment groups (valproate, lithium, carbamazepine, and combina­tion mood stabilizer therapy) were formed based on the mood stabilizers patient received. Differences in annual health care use and expenditures were estimated between propensity score matched treatment and comparison groups controlling for comorbidity, prior utilization, demographic, and health provider specialty.

Results: During the 1?year observation period, subjects in treatment groups filled an average of 200-days supply of adjunctive mood stabilizers. These adjunctive mood stabilizer recipients had significantly longer antipsychotic treatment durations than the subjects who did not have exposure to mood stabilizers (valproate + antipsychotic vs. antipsychotic only, net difference: 56.47 days, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: 90.25 days, p < 0.0001; carbamazepine + antipsychotic vs. antipsychotic only, net difference: 41.27 days, p = 0.0439; multiple mood stabilizers + anti­psychotic vs. antipsychotic only, net difference: 83.14 days, p < 0.0001). The intensive pharmacotherapy associated with treatment groups resulted in $900–$1300 higher pharmacy costs than the comparison groups (valproate + antipsychotic vs. antipsychotic only, net difference: $1218.43, p < 0.0001; lithium + antipsychotic vs. antipsychotic only, net difference: $985.79, p = 0.0015; carbamazepine + antipsychotic vs. anti­psychotic only, net difference: $911.63, p = 0.0497; multiple mood stabilizers + antipsychotic vs. antipsychotic only, net difference: $1281.91, p < 0.0047). However, there were no statistically significant differences for total health expenditures, hospitalizations, emergency room visits, and nursing home admissions between propensity-matched treatment and control groups.

Conclusions: There were no differences in health care costs or utilization of ER, long-term care, and inpatient services between schizophrenia patients who did and did not receive adjunctive mood stabilizer; however, longer anti­psychotic treatment durations were observed in patients receiving adjunctive mood stabilizers. Interpretation of these results is limited by the unknown selection bias between the treatment and the comparison groups and the relatively small number of patients in some treatment groups. The development of a better-controlled study to further evaluate this treatment regimen is warranted.     

Antiviral drugs in influenza: an adjunct to vaccination in some situations

(1) Influenza is a common acute respiratory disease due to a virus that causes annual seasonal epidemics. Three major pandemics occurred in the 20th century, in 1918-1919, 1957 and 1968, mainly due to genetic variants of type A influenza virus. (2) In temperate regions the incidence of hospitalisation increases during annual influenza epidemics. More than 90% of deaths linked to influenza involve people over 65 years of age. (3) The clinical manifestations of influenza virus infection are non specific. The main complications are secondary bacterial respiratory tract infections (especially pneumonia); those most at risk are people over 65, infants less than one year old, and people with underlying chronic disorders (pulmonary, cardiac, renal or metabolic) or immune deficiencies. (4) Vaccination is the main preventive measure. During most years the vaccine strain closely matches the epidemic strain. In relative terms, vaccination of people over 65 reduces the number of deaths linked to influenza by about 80%, hospitalisation and pneumonia by about 50%, and symptomatic influenza by about 30%. Yearly vaccination is recommended for younger people with serious chronic disease. (5) Three antiviral drugs are currently approved in France for prevention or treatment of influenza: amantadine and the neuraminidase inhibitors zanamivir and oseltamivir. (6) Efficacy of antiviral drugs has not been evaluated in comparative randomised trials in which death and influenza complications were the primary outcome measures. (7) A systematic review of 20 comparative randomised trials involving about 2500 healthy people showed that amantadine reduced the frequency of flu-like syndromes by about 7% in absolute terms (26.3% versus 33.1% with placebo). Zanamivir and oseltamivir have only been shown to reduce the frequency of serologically confirmed episodes of influenza (0.4% to 2.5%, compared to 4.4% to 14.9% with placebo). (8) In a randomised placebo-controlled trial of oseltamivir, involving 548 institutionalised subjects over 65 years of age, more than 80% of whom had been vaccinated, respiratory tract infections were less frequent in the oseltamivir group, but the relevance of this result is undermined by the small number of observed cases. (9) Efficacy of antiviral drugs on avian influenza (bird flu) was studied during a 2003 Dutch outbreak due to a type A/H7N7 virus. Among the 38 exposed persons who were treated, about 3% developed symptoms, compared with about 10% of 52 exposed persons who refused treatment (p = 0.38). The low statistical power and the lack of randomisation rule out any firm conclusions on preventive effects. (10) The three antiviral drugs have different profiles of adverse effects and drug interactions. Amantadine carries a risk of neuropsychological, atropinic and dopaminergic adverse effects, and can interact with drugs that have similar effects. Zanamivir carries a risk of life-threatening bronchospasm. Oseltamivir was approved relatively recently and its full spectrum of adverse effects is not yet known; its main adverse effects appear to be mild gastrointestinal disturbances, although a few cases of serious cutaneous reactions have been reported. (11) In vitro resistance to the three drugs has been demonstrated, but the possible clinical and epidemiological consequences are unclear. (12) In situations warranting antiviral therapy for the prevention of influenza, oseltamivir, at a dose of 75 mg/day for 10 days, is the drug with the best risk-benefit balance. Its use should be limited to situations where a major potential benefit exists in order to avoid selection for resistant strains. (13) Testing of oseltamivir in children is limited. Oseltamivir should be avoided during pregnancy, because of evidence that it may harm the unborn child. (14) In practice, the use of antiviral drugs in otherwise healthy adults and children is not generally recommended. (15) Despite the lack of convincing data regarding the efficacy of oseltamivir in preventing complications of influenza, its effect on documented infections suggests it may be useful for unvaccinated individuals who are at high risk of infection and severe complications. Under these conditions, treatment should be started within 48 hours after contact with a person who has flu-like symptoms during a seasonal epidemic; residents in institutions in which influenza cases occur may also qualify for preventive treatment. Other preventive measures should also be used, including immediate vaccination, case isolation, use of face masks, and more frequent hand washing. (16) During seasonal influenza epidemics due to viral strains against which the current vaccine is of limited effectiveness, the utility, target populations and optimal duration of preventive antiviral treatment must be determined by examining the groups most at risk and the severity of complications. (17) Most flu-like syndromes are not due to the influenza virus, and the preventive effect of antiviral drugs on complications in persons at risk has not yet been demonstrated. (18) In practice, antiviral drugs are not an alternative to influenza vaccination, but may be a useful adjunct in some situations. It is best to limit their use to short-term prophylaxis of vulnerable persons in situations where the risk of contracting influenza virus infection is high.     

The pharmacological management of severe influenza infection – ‘existing and emerging therapies’

Introduction: Over the last century several influenza outbreaks have traversed the globe, most recently the influenza A(H1N1) 2009 pandemic. On each occasion, a highly contagious, virulent pathogen has emerged, leading to significant morbidity and mortality amongst those affected.

Areas covered: Early antiviral therapy and supportive care is the mainstay of treatment. Treatment should be started as soon as possible and not delayed for the results of diagnostic testing. Whilst oseltamivir is still the first choice, in case of treatment failure, oseltamivir resistance should be considered, particularly in immunosuppressed patients. Here we review the antivirals currently used for management of influenza and explore a number of investigational agents that may emerge as effective antivirals including parenteral agents, combination antiviral therapy and novel agents in order to adequately target influenza virulence.

Expert Commentary: New tools for rapid diagnosis and susceptible strains will help if a patient is not improving because of a resistant strain or an inadequate immune response. Further randomized control trials will be conducted to investigate the use of new antivirals and co-adjuvant therapies that will help to elucidate the process of immune modulation, particularly in immunocompetent patients.     

Oseltamivir: new indication. Prevention of influenza in at-risk children: vaccination is best

(1) Complications of influenza are rare in children and mainly affect children with serious birth defects or chronic underlying disorders such as cystic fibrosis and severe asthma. (2) Oseltamivir is the second antiviral drug, after amantadine, to be marketed in the European Union for the prevention of influenza in children aged from 1 to 12 years. (3) The clinical evaluation of oseltamivir in this indication is limited to a retrospective subgroup analysis of an unblinded trial versus no treatment. The data suggest that oseltamivir is at best only modestly effective in reducing the incidence of laboratory-confirmed influenza (about 7% versus 19%). With zanamivir, the incidence of laboratory-confirmed influenza was about 2%, versus 6% to 15% in the placebo groups in several trials. As of 5 January 2007, zanamivir had not been marketed for paediatric use in France. With amantadine, the incidence was about 3% to 9%, depending on the trial, versus 9% to 30% on placebo. Amantadine has only been shown to have an effect on type A influenza virus and is only available in tablet form (unsuitable for young children). In summary, there is no firm evidence that antiviral prophylaxis reduces the rate of influenza complications in children. (4) Severe cutaneous and neurological adverse effects have been reported in children treated with oseltamivir. Pharmacovigilance studies show a risk of angioedema and toxic epidermal lysis with oseltamivir. (5) There are worrisome reports of influenza virus strains resistant to available antivirals. (6) In practice, oseltamivir is not sufficiently effective or safe for the prevention of influenza in children, which does not justify its use other than in clinical trials.     

Oseltamivir-resistant influenza A(H1N1) 2009 virus in Greece during the post-pandemic 2010-2011 season

Information on the drug susceptibility of influenza epidemic strains is important for antiviral resistance monitoring. In Greece, the 2009-2010 pandemic waves were very mild and seroprevalence rates remained low after this influenza season, resulting in exclusive detection of the pandemic strain during the 2010-2011 influenza season. In the present study during the post-pandemic 2010-2011 season, 50 consecutive influenza A(H1N1) 2009 virus-positive samples from patients hospitalised in Greek hospitals were analysed for resistance to the neuraminidase inhibitor oseltamivir. All patients were hospitalised with severe influenza complications and had previously received oseltamivir. Influenza A(H1N1) 2009 virus detection and testing for oseltamivir resistance were performed with real-time PCR amplification assays. The H275Y substitution associated with resistance to oseltamivir was identified in two immunocompetent patients who received oseltamivir treatment for 3 days and 5 days, respectively. In both cases, patients were discharged in good condition despite development of resistance to antiviral treatment.     

Neuraminidase inhibitors for influenza B virus infection: Efficacy and resistance

Many aspects of the biology and epidemiology of influenza B viruses are far less studied than for influenza A viruses, and one of these aspects is efficacy and resistance to the clinically available antiviral drugs, the neuraminidase (NA) inhibitors (NAIs). Acute respiratory infections are one of the leading causes of death in children and adults, and influenza is among the few respiratory infections that can be prevented and treated by vaccination and antiviral treatment. Recent data has suggested that influenza B virus infections are of specific concern to pediatric patients because of the increased risk of severe disease. Treatment of influenza B is a challenging task for the following reasons:

1.

NAIs (e.g., oseltamivir and zanamivir) are the only FDA-approved class of antivirals available for prophylaxis and treatment of influenza.     

One-year costs of ischemic heart disease among patients with acute coronary syndromes: findings from a multi-employer claims database*

ABSTRACT

Objective: Acute coronary syndromes (ACS) are life-threatening disorders requiring intensive medical management or invasive cardiovascular procedures. Limited data exist on the costs and resource utilization associated with ACS.

Methods: This retrospective single-cohort study analyzed administrative claims data from employer-sponsored plans for patients with an ACS hospitalization in 2001–2002. A 1?year follow-up period was used, and patients who were under age 35 or had an ACS diagnosis in the 12 months before the hospitalization were excluded. Costs were reported in 2005 US dollars.

Results: We identified 16?321 patients hospitalized for ACS during the study period. Mean (±?SD) age was 55.6 (±?6.7) years, 66.7% were male, and 46.3% underwent a revascularization procedure during their initial hospital­ization. Mean length of stay for the initial hospitalization was 4.6 days (median: 3.0; IQR: 2.0–5.0), and per-patient expenditures averaged $22?921 (median: $13?960; IQR: $6839–28?588). During the follow-up period, 21% of patients were rehospitalized for ischemic heart disease (IHD), and the cost of rehospitalization averaged $28?637. Additionally, in the year following the inpatient admission, 50% of patients were prescribed antiplatelet or anti­coagulant medications, and 90% of patients were prescribed lipid-lowering, antihypertensive, or anti­arrhythmic medications. IHD-related expenditures after the initial inpatient stay averaged $9425 (median: $2800; IQR: $899–7577); 61% of these costs were due to rehospitalization. Total first-year costs averaged $32?345 (median: $21?653; IQR: $10?642–41?106).

Limitations: Diagnoses could not be verified through medical charts. Payments for Medicare patients were not assessed given our focus on the working-age population.

Conclusions: In this employer-sponsored health plan population, the costs of inpatient and outpatient IHD-related care were high. Future studies should evaluate the impact of improved patient management on post-discharge costs.     

Oseltamivir: cutaneous and neurological adverse effects in children

(1) Oseltamivir is an antiviral drug used for influenza. It has only been tested in children to a limited extent. (2) A few deaths have been reported in children receiving oseltamivir, in some cases due to neurological causes. All of these deaths occurred in Japan. The European Medicines Agency has described 2 deaths, both attributed to suicide, in adolescents aged 14 and 17 who were taking oseltamivir. Both patients had developed behavioural disorders before their death. (3) According to the US Food and Drug Administration, neuropsychiatric disorders were reported in 32 children (mainly in Japan), and include delirium, behavioural disorders, hallucinations, convulsions and confusion. (4) Disturbing neurological toxicity has been observed in young rats exposed to oseltamivir, leading the American and European agencies to warn against the use of oseltamivir in infants less than one year old. (5) Severe cutaneous adverse effects, including cases of Lyell syndrome, were reported in children taking oseltamivir. (6) In practice, oseltamivir is only modestly effective in the prevention of influenza and treatment of suspected influenza. There is no evidence of an effect on complications of the flu in adults or children at higher risk. The possibility of serious adverse effects should be weighed against the limited benefit of oseltamivir.